This application is a 371 of PCT/JP99/01335 filed Mar. 17, 1999.
The present invention relates to a prophylactic and therapeutic drug for brain tissue impairment.
The brain discharges a multi-pronged function including regulation of autonomic nervous system, control of the motion, understanding of the senses, and high-order mental activities such as thinking. When the cerebral blood flow is compromised, the uptake of glucose and oxygen which are essential to the brain function ceases and the brain is no longer able to maintain its homeostasis, with the result that the workings of the brain are seriously handicapped.
Brain tissue impairment results from insufficiency of cerebral blood flow due to various factors or as the result of a complicated interaction of systemic factors such as cardiopathy. Furthermore, the brain tissue is impaired not only by encephalothlipsis secondary to brain trauma, cerebral edema, brain tumor, etc. but also by decreases in cerebral blood flow due to systemic events involving a marked depression of blood pressure such as massive hemorrhage, myocardial infarction, administration of a hypotensive drug, and arrhythmia. The disease caused by such impairment of the brain tissue includes, but is not limited to, cerebral vasospasm, cerebral thrombosis, cerebral infarction, cerebral embolism, intracerebral hemorrhage, subarachnoid hemorrhage, hypertensive encephalopathy, transient ischemic attack, multi-infarct dementia, cerebral arteriosclerosis, and Huntington""s disease.
The current pharmacotherapy of brain tissue impairment includes administration of cerebral vasodilators such as cinnarizine, cyclandelate, and pentoxifylline; cerebral metabolism activator such as meclofenoxate hydrochloride, thioctic acid, and GABA; anticoagulants such as heparin sodium; thrombolytic drugs such as urokinase; and platelet aggregation inhibitors such as aspirin and dipyridamole. However, none of those drugs are sufficiently effective; hence the problems remain unsolved.
As recently reported, leupeptin having calpain-inhibitory activity protects neurons against damage by cerebral ischemia [Lee K. S., Frank S., Vanderklish, P., Arai A., Lynch G., Proc. Natl. Acad. Sci., 88, 7233-7237 (1991), Rami A., Krieglstein J., Brain Res., 609, 67-70 (1993), WO92/11850]. However, in those reported studies, the drug is directly administered into the animal cerebral ventricle in consideration of the inability of leupeptin to cross the blood-brain barrier. That is to say, the technology cannot realistically be applied to man. It is disclosed in WO92/11850 that, administered intraperitoneally, certain compounds such as calpain inhibitor I were found to protect neurons from excitotoxic factors. However, calpain inhibitor I is reportedly cytotoxic [Inoue S., Sharma R. C., Schimke R. T., Simoni R. D., J. Biological Chem., 268 (8), 5894-5898 (1993)] and cannot be safely used in man. It has recently been reported that, administered intravenously, the calpain inhibitor Cbz-Val-Phe-H inhibited cytopathy due to cerebral ischemia in rats [Hong S. C., Goto Y., Lanzino G., Soleau S., Kassell N. F., Lee K. S., Stroke, 25 (3), 663-669 (1994)] but its action is not sufficiently strong and, therefore, the drug has not been clinically applied as yet.
The present invention has for its object provision of a prophylactic and therapeutic drug for brain tissue impairment, which has overcome the above-mentioned disadvantages, and of a method for prophylaxis and therapy of such impairment.
The inventors of the present invention endeavored to develop a prophylactic and therapeutic drug for brain tissue impairment, which would cross the blood-brain barrier with ease and be safe to use, and discovered that a compound of the following formula (I) 
wherein R1 represents an alkyl group having 1-4 carbon atoms or an aryl group having 6-10 carbon atoms which is optionally substituted; R2 and R3 may be the same or different and each represents hydrogen or an alkyl group having 1-4 carbon atoms or R2 and R3 may jointly form a ring. having 3-7 carbon atoms; R4 represents a lower alkyl group which is optionally substituted by aryl, cycloalkyl, or aromatic heterocyclic residue, and a pharmaceutically acceptable salt thereof exhibit remarkable prophylactic or therapeutic efficacy against brain tissue impairment. The present invention has been developed on the basis of the above finding.
In the context of the present invention, brain tissue impairment includes not only impairment of brain tissues associated with cerebral ischemia or cerebral hemorrhage but also secondary impairment of brain tissue due to encephalothlipsis caused by brain trauma, cerebral edema, brain tumor, etc. and impairment of brain tissue associated with circulatory insufficiency of the brain due to systemic events involving a marked depression of blood pressure such as massive hemorrhage, myocardial infarction, administration of a hypotensive drug, arrhythmia, and so forth.